DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome

EBioMedicine. 2015 Jan 17;2(2):120-34. doi: 10.1016/j.ebiom.2015.01.010. eCollection 2015.

Abstract

Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.

Keywords: Cell cycle regulation; Cerebral cortex development; DS, Down syndrome; DYRK kinases; IP, intermediate progenitor; Intellectual disability; NSC, neural stem cell; Neurodevelopmental disorders; RG, radial glia; SVZ, subventricular zone; Trisomy 21; VZ, ventricular zone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / pathology
  • Cyclin D1 / metabolism*
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • G1 Phase / genetics
  • Gene Dosage / genetics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism*
  • Telencephalon / cytology
  • Trisomy / genetics

Substances

  • CCND1 protein, human
  • Cyclin D1
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases